Cao Xiaobo, Rodarte Charles, Zhang Lidong, Morgan Clinton D, Littlejohn James, Smythe W Roy
Section of Surgery Research, Department of Surgery, Scott & White Memorial Hospital and Clinic, 2401 South 31st Street, Temple, TX 76508, USA.
Cancer Biol Ther. 2007 Feb;6(2):246-52. doi: 10.4161/cbt.6.2.3626. Epub 2007 Feb 26.
Mesothelioma is a neoplasm of the pleura that is currently incurable by conventional therapies. Previously, we demonstrated that mesothelioma overexpresses BCL-X(L), an anti-apoptotic member of the BCL-2 family. In addition, we have shown that down regulation of BCL-X(L) using a BCL-X(L) antisense oligonucleotide engenders mesothelioma apoptotic cell death in vitro and in vivo. The purpose of this study is to evaluate the efficacy of bcl2/bcl-x(L) inhibitor, 2-methoxy antimycin A3, in inducing apoptosis and increasing chemo-sensitivity in vitro and in vivo. Several bcl-x(L) high-expression tumor cell lines and one normal human cell line were exposed to 2-methoxy antimycin A3. 2-methoxy antimycin A3 demonstrated significant growth inhibition only in these tumor cell lines, with little effect on normal human cells. Treatment with 2-methoxy antimycin A3 alone resulted in a dramatic increase in the induction of apoptosis in the cancer cells. Apoptosis occurs through decreasing mitochondrial membrane potential and caspase activation. Notably, treatment with 2-methoxy antimycin A3 does not alter BCL-2 family protein expression. Synergistic inhibition of tumor growth by the coadministration of cisplatin and 2-methoxy antimycin A3 was observed in both in vitro and in vivo experiments. Together, these findings indicate that exposure of cancer cells to small molecule Bcl-2/x(L) inhibitors such as 2-methoxy antimycin A3 alone, or in the combination with other chemotherapeutics, may represent a novel therapeutic strategy in treatment of cancer, especially mesothelioma.
间皮瘤是一种胸膜肿瘤，目前传统疗法无法治愈。此前，我们证明间皮瘤过度表达BCL-X(L)，它是BCL-2家族的一个抗凋亡成员。此外，我们还表明，使用BCL-X(L)反义寡核苷酸下调BCL-X(L)可在体外和体内引发间皮瘤细胞凋亡。本研究的目的是评估bcl2/bcl-x(L)抑制剂2-甲氧基抗霉素A3在体外和体内诱导细胞凋亡以及增强化疗敏感性的疗效。将几种BCL-X(L)高表达肿瘤细胞系和一种正常人细胞系暴露于2-甲氧基抗霉素A3。2-甲氧基抗霉素A3仅在这些肿瘤细胞系中显示出显著的生长抑制，对正常人细胞几乎没有影响。单独用2-甲氧基抗霉素A3处理导致癌细胞凋亡诱导显著增加。细胞凋亡通过降低线粒体膜电位和激活半胱天冬酶而发生。值得注意的是，用2-甲氧基抗霉素A3处理不会改变BCL-2家族蛋白的表达。在体外和体内实验中均观察到顺铂和2-甲氧基抗霉素A3联合使用对肿瘤生长的协同抑制作用。总之，这些发现表明，癌细胞单独暴露于小分子Bcl-2/x(L)抑制剂如2-甲氧基抗霉素A3，或与其他化疗药物联合使用，可能代表一种治疗癌症特别是间皮瘤的新治疗策略。
